One in ten of the persons age 65+ are affected by Alzheimer?s disease (AD), causing enormous social and economic burden to the United States. To date only five medications have been approved by the FDA for the treatment of the symptoms of AD, but none of them slows or stops the disease progression. With the recent repeated failures of AD drugs on the ?-secretase inhibitors, the need for an effective AD drug became even more pressing and it also prompted the development of the new drugs on alternative mechanisms of actions. Accumulating evidence suggests that autophagy-lysosome pathway (ALP)-associated defects play a crucial role in AD pathogenesis and this pathway is considered a potential target for the development of AD drugs. Recently, transcription factor TFEB was found to increase biogenesis of new lysosomes and the entire ALP by activating more than 35 genes. TFEB overexpression resulted in marked reduction of both PHF-tau and amyloid plaque burden in mouse models of AD. Additionally, TFEB has also demonstrated efficacy in clearing protein aggregates in models of Parkinson?s and Huntington?s diseases. Moreover, TFEB stimulates both endocytosis and exocytosis, which additionally enhances cellular clearance. Thus, we hypothesize that TFEB activation may be a promising mechanism to effectively modify AD progression and TFEB activators may be developed into disease modifying drugs for AD. Aiming to develop TEFB activators into disease modifying drugs for AD, in a joint research project between Brilliant BioSciences Inc and Torrey Pines Institute for Molecular Studies, we have identified a small-molecule hit exhibiting potent TFEB activation and producing efficacy in reducing A? levels in cell lines. The hit passed through the blood brain barrier in mice, and had a therapeutic window of 250 in rat primary cortical neurons and AD fibroblasts. These data suggest that the hit may be promising for the development of the disease modifying drug for AD. However, the hit is quite hydrophobic with a cLogP value beyond the 2?5 range. Therefore, in the STTR phase I study we will conduct medicinal chemistry to optimize the hit to increase its hydrophilicity while improving/maintaining the activity toward TFEB. We will also test the analogs for their biological activities such as dephosphorylation of TFEB and nuclear translocation of EGFP-TFEB in AD fibroblasts, and examine their toxicity in both primary neurons and fibroblasts derived from AD patients. The best compound will then be tested for the effect on neurofibrillary tangle pathology and amyloid plaque burden using SAMP8 mice as a model of AD. By the end of the project period, the goal is to obtain one or more compounds that have a cLogP in the range of 2-5, activates TFEB dephosphorylation and nuclear translocation in AD fibrolasts at a concentration of ?100 nM, and produces clearance of plaque or tangle burden in the SAMP8 mouse model of AD. We will carry this lead forward to the Phase II study for further development of the disease modifying drugs for AD.